EFFECT OF ATP BINDING CASETTE SUBFAMILY B MEMBER 1, 5-HYDROXYTRIPTAMINE -3B RECEPTOR AND CYP2D6 GENE POLYMORPHISMS AND SOME RISK FACTORS TO THE ANTIEMETICS RESPONSE THERAPY IN CANCER PATIENTS WITH HIGHLY EMETOGENIC CYTOTOXIC DRUG IN DR. SARDJITO HOSPITAL YOGYAKARTA
Dyah Aryani Perwitasari, M.Si.,Apt., Prof. dr. M. Hakimi, Ph.D.,Sp.OG(K)
2011 | Disertasi | S3 Kedokteran Umum-
Nausea and vomiting are the most distressful side effects of cytotoxic drugs in cancer patients. However, the current antiemetic efficacy is about 70%-80% in patients treated with highly-emetogenic cytotoxic drugs. One of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins which play a role in metabolism, transport and receptors related to antiemetic drugs. Aim of this study was to assess the impact of the variants of ABCB1 drug transporter, 5- HT3B receptors and CYP2D6 genes on antiemetics response to patient with highly emetogenic cytotoxic and the patients’ characteristic that influence to response of therapy at Dr. Sardjito Hospital Yogyakarta. This study used prospective non-interventional cohort study. The study population were cancer subjects in the Oncology Department of Dr Sardjito Hospital, Yogyakarta, Indonesia, who were treated with a cisplatin dosage ≥ 50 mg/m 2 as monotherapy or in combinations, ondansetron 8 mg, iv and dexametason 8 mg, iv. The pharmacogenetic assay used subjects saliva as the samples. The severity of nausea were identified by Nausea Visual Analog Scale, while the frequency of vomiting were collected during 24 hours before chemotherapy and 4 x 24 hours after the last dose of cytotoxic drug administration (single or multiple days regimen), by using patients’ daily emetogenic record. subjects’ quality of life were measured by EORTC QLQ C 3.0, which has been translated and validated into an Indonesian version. subjects were asked to fill in the questionnaires before and 4 x 24 hours after cytotoxic drug administration. Three SNPs of 5-HT3B receptor gene; rs45460698 (deletion_AAG in 5’-UTR position), rs4938058 (intron) , and rs7943062 (3’ near gene), three SNPs of ABCB1 gene; rs104562 (exon 26), rs2032582 (exon 22), rs 1128503 (exon 12) and three SNPs of CYP2D6; rs16947 (CYP2D6*2), rs1135840 (CYP2D6*4), rs106582 (CYP2D6*10) were selected from the National Center for Biotechnology Information SNP database. The selection of the SNPs considered minimal genotype frequency of 10% or more, validated SNPs and Linkage Disequilibrium (LD) with other SNPs which have been investigated in previous studies. DNA was quantified using Nanodrop (Isogen, Maarssen, The Netherlands). Genotypes were established using Taqman assays and analysed on ABI 7500 realtime PCR System from Applied Biosystems (Nieuwerkerk aan den IJssel, The Netherlands). The univariate analysis such as chi-square for categorical scale, the Ttest for two groups of continuous scale and Anova-test for more than two groups of continuous scale were used to define the association between subjects characteristic, variants of ABCB1 drug transporter gene, 5-HT3B receptor gene and CYP2D6 gene and the primary and secondary outcome. The chi-square for categorical scale, the Ttest for two groups of continuous scale and the Anova-test for more than two groups of continuous scale were used to exclude interactions between subjects characteristic and the variants of ABCB1 drug transporter gene, 5-HT3B receptor gene and CYP2D6 gene. The binary logistic analysis was used to know the risk factors of primary and secondary outcome. The polymorphisms of ABCB1, 5HT3B receptor and CYP2D6 genes did not affect ondansetron response in Indonesian cancer subjects during the acute phase. The cancer subjects with CTG wild type experienced lower risk of developing delayed emesis (RR=0.64, 95% CI: 0.43-0.95). Subjects treated with cisplatin as single agent of cytostatic agent may increase the risk of acute nausea twice greater than patients treated by combination cytostatic agents (RR= 2.07; 95% CI: 1.12-3.84). Subjects without history of motion sickness experienced lower risk of developing acute vomiting (RR=0.60; 95% CI: 0.37-0.99). Subjects with severe CINV in delayed phase experienced deterioration quality of life functions and experienced more severe symptoms after chemotherapy. In general, all subjects, with and without delayed emesis, showed the deterioration of quality of life after chemotherapy. After adjusted for the other haplotypes of ABCB1, CYP2D6 phenotype, the subjects characteristics and interactions between those variables and CTG haplotypes, we found that subjects with CTG wildtype experienced lower risk of developing delayed emesis than the CTG carriers (RR= 0.11; 95% CI: 0.01-0.82). After adjusted for the other variables such as; haplotypes of 5-HT3B receptor gene, CYP2D6 phenotype, subjects’ characteristics and interactions between them, we found that subjects without history of motion sickness who received cisplatin experienced significant lower risk of acute nausea (RR=0.35; 95% CI: 0.16-0.77). After adjusted for the other variables such as; haplotypes of 5-HT3B receptor gene, CYP2D6 phenotype, subjects’ characteristics and interactions between them we found that subjects without perceptions of having nausea and vomiting after chemotherapy and without history of motion sickness experienced lower risk of developing acute vomiting (RR=0.11; 95% CI: 0.03-0.83).
Kata Kunci : pharmacogenetic, ondansetron, EORTC QLQ-C30, ondansetron, Indonesia cancer patients
